PROJECT SUMMARY The present proposal, in response to PAR-17-029, seeks to advance our understanding of how crosstalk between adipose tissue (AT) and the brain may contribute to the pathophysiology of Alzheimer's disease (AD). The scientific premise is based on the fact that while body mass index (BMI) is an independent predictor of AD in both mid- and late-life, the association with this crude global measure of obesity is confounded by aging- related changes in AT distribution and function. Although the underlying mechanisms remain to be elucidated, it is clear that BMI is not sufficient to fully understand the obesity-associated risks for AD. Diet influences the risk of both obesity and AD, and investigating dietary interventions that can modulate both AT and the brain may provide critical insight into the overlapping molecular pathways linking these diseases. Our preliminary data suggest that greater amounts of AT in central / visceral (VAT) depots and lower amounts of AT in peripheral / subcutaneous (SAT) depots are associated with a cerebrospinal fluid (CSF) biomarker profile indicative of increased AD pathology. Moreover, minimizing the loss of protective SAT depots following a ketogenic diet may favorably impact AD pathology. To confirm and extend these findings, we propose to conduct an ancillary study to the Brain Energy for Amyloid Transformation in AD (BEAT-AD) trial, a phase 2 randomized clinical trial designed to examine the effects of a 4-month Modified Mediterranean Ketogenic (MMK) diet versus an American Heart Association (AHA) low-fat diet on brain health in 120 adults (age: 55 to 85 years) with amnestic mild cognitive impairment (aMCI) (R01AG055122; PI: Craft). The proposed study will leverage ongoing study procedures, data, and samples to generate new data on AT distribution and function, including their relationship with AD biomarkers and their modulation by diet. Specifically, CT imaging will be leveraged to quantify changes in the cross-sectional area and density of VAT, SAT, and intermuscular AT in the abdomen and thigh, as well as fatty infiltration of liver and skeletal muscle. FDG-PET imaging will also be leveraged to quantify changes in glucose uptake (i.e., metabolic activity) in AT depots of interest. Finally, stored blood and CSF will be used to assess changes in circulating adipokines and AT-derived exosomes. To complement the ongoing collection of CSF, FDG-PET, amyloid PET, and structural/functional MRI, the proposed study will also add 18F-AV-1451 tau PET in a subset of participants (n=60), which will enhance the categorization of participants across the AD spectrum as defined by the NIA-AA Research Framework. This timely, cost-effective, and innovative study will not only expand the scope and impact of the parent trial, but will also address important gaps in the field. Investigating AT distribution and function in the context of the MMK diet may reveal novel targets that are amenable to intervention and new therapeutic agents that can alter the trajectory of AD.